Enhancer RNAs step forward: new insights into enhancer function

Abstract

Enhancers confer precise spatiotemporal patterns of gene expression in response to developmental and environmental stimuli. Over the last decade, the transcription of enhancer RNAs (eRNAs) – nascent RNAs transcribed from active enhancers – has emerged as a key factor regulating enhancer activity. eRNAs are relatively short-lived RNA species that are transcribed at very high rates but also quickly degraded. Nevertheless, eRNAs are deeply intertwined within enhancer regulatory networks and are implicated in a number of transcriptional control mechanisms. Enhancers show changes in function and sequence over evolutionary time, raising questions about the relationship between enhancer sequences and eRNA function. Moreover, the vast majority of single nucleotide polymorphisms associated with human complex diseases map to the non-coding genome, with causal disease variants enriched within enhancers. In this Primer, we survey the diverse roles played by eRNAs in enhancer-dependent gene expression, evaluating different models for eRNA function. We also explore questions surrounding the genetic conservation of enhancers and how this relates to eRNA function and dysfunction.

eRNA-IDO: a one-stop platform for identification, interactome discovery and functional annotation of enhancer RNAs

“…Co-expression relationships have been widely used to annotate the functions of eRNAs [31-33]. Additionally, eRNAs were reported to exert regulatory functions through interacting with other biomolecules, including transcription factors (TFs) [34-36], RNA binding proteins (RBPs) [4, 37, 38], and target gene activated by E-P loops [39, 40]. These interactions make the regulatory network a powerful tool for eRNA functional annotation, resembling to those we used for other ncRNAs [12, 41-44].…”

Are non‐protein coding RNAs junk or treasure?

“…[101] Nevertheless, their large number, estimated to be in the hundreds of thousands, [100] contribution to super-enhancers that involve the rapid, transient transcription of eRNAs and their phase separation into eRNA-protein granules, fast evolution under selection for adaptive radiation, and the fact that the vast majority of single nucleotide polymorphisms in the human genome with causal links to complex diseases map to eRNA genes lend them functional relevance. [101][102][103][104][105][106] Furthermore, the observation that most eukaryotic transcription factor proteins have confusing and enigmatic functions, as well as ill-defined structures, suggests that they have been interpreted using a conceptual framework that misses cooperating eRNAs as a critical link. [40] In this modern view of eukaryotic gene expression, only those transcription events will occur that are sufficiently robustly proofread by a sequence of kinetically controlled, reversible assembly events that have to enhance each other and outcompete a vast number of possible alternative events.…”

The transcripts of a gastrula-premarked enhancer prime posterior tissue development through cross-talk with morphogen effector

“…Enhancer RNAs (eRNAs), which are transcribed from corresponding enhancers and often pre-loaded with RNA polymerase II and H3K27ac, could be used to represent the enhancer activity and also be involved in the regulation of gene expression and cell fate determination (33)(34)(35)(36)(37). To further refine the scope of potential functional DREs, we determined the abundance of eRNA transcripts for the top-30 DREs across various tissues of embryos at different stages (E7.0, E7.5, E9.5) using RT-qPCR (Fig.…”